Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates.
It is unclear how polyglutamine expansion is associated with the pathogenesis of Huntington disease (HD). Here, we provide evidence that polyglutamine expansion leads to the formation of large intracellular aggregates in vitro and in vivo. In vitro these huntingtin-containing aggregates disrupt normal cellular architecture and increase in frequency with polyglutamine length. Huntingtin truncated at nucleotide 1955, close to the caspase-3 cleavage site, forms perinuclear aggregates more readily than full-length huntingtin and increases the susceptibility of cells to death following apoptotic stimuli. Further truncation of huntingtin to nucleotide 436 results in both intranuclear and perinuclear aggregates. For a given protein size, increasing polyglutamine length is associated with increased cellular toxicity. Asymptomatic transgenic mice expressing full-length huntingtin with 138 polyglutamines form exclusively perinuclear aggregates in neurons. These data support the hypothesis that proteolytic cleavage of mutant huntingtin leads to the development of aggregates which compromise cell viability, and that their localization is influenced by protein length.
Martindale
D
D
Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.
Hackam
A
A
Wieczorek
A
A
Ellerby
L
L
Wellington
C
C
McCutcheon
K
K
Singaraja
R
R
Kazemi-Esfarjani
P
P
Devon
R
R
Kim
S U
SU
Bredesen
D E
DE
Tufaro
F
F
Hayden
M R
MR
D000818:Animals; D002449:Cell Aggregation; D002460:Cell Line; D002470:Cell Survival; D000882:Haplorhini; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism*; D010455:Peptides; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D014162:Transfection
C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D011994:Recombinant Proteins; C097188:polyglutamine